Cirrhosis of liver is a pathologic entity defined as diffuse hepatic fibrosis with the replacement of the normal liver architecture by nodules.1 Although cirrhosis of liver is strictly speaking a histologic diagnosis, a combination of clinical, laboratory and imaging feature can help in confirming a diagnosis of cirrhosis of liver2. Cirrhosis of liver is associated with large number of complications. Some of the common complications are ascites, hepatic encephalopathy, hepatic failure, variceal bleeding, hepatorenal syndrome, frequent infections, malnutrition and increased risk of liver cancer(hepatocellular carcinoma). Electrolyte abnormalities are frequently encountered in patients with advanced liver disease.3 Hyponatremia is one of the most common electrolyte abnormality seen in patients of decompensated cirrhosis of liver.2 Hyponatremia has three clinical types: hypervolemic, euvolemic, and hypovolemic. In patients with cirrhosis, the majority of cases (90%) have hypervolemic (dilutional) hyponatremia. In 10% of cases, hyponatremia is hypovolemic, typically from overdiuresis. Chronic hyponatremia presents in up to 22% of people with cirrhosis of liver.4 The prevalence of severe hyponatremia( S.Sodium< 120 mEq/L)in cirrhosis of liver is 1.2%.4 Prolonged hyponatremia may cause irreversible neurological damage.5Pretransplant hyponatremia was a significant risk factor for short-term graft loss and postoperative complications including sepsis, renal failure and neurological disorders 6 . In addition, serum sodium level was a significant independent predictive factor for post-transplant short-term graft loss.The cause of the hypervolemic hyponatremia in patients with cirrhosis of liver is related to a marked reduction in systemic vascular resistance, especially in the splanchnic circulation and compensatory activation of endogenous vasoconstrictors including the renin-angiotensin system, the sympathetic nervous system and antidiuretic hormone (ADH).Hyponatremia can negatively affect short and long term prognosis in cirrhosis of liver. Recognizing this adverse impact certain organ allocation systems have started to use MELD-Na as the allocation strategy for transplant. However despite this widespread recognition of the negative association of hyponatremia, few pro-active therapies are in routine clinical use to correct it7. Current management varies from close monitoring, diuretic withdrawal and fluid restriction in selected cases. AIM To quantify the difference in serum sodium levels before and after intravenous albumin therapy.

The present study was conducted in the Department of Gastroenterology at Pushpawati Singhania Research Institute (PSRI), located on Press Enclave Road, Sheikh Sarai Phase 2, New Delhi. The study was conducted within the time frame of Dec 2022 to July 2024. The study population included adult hospitalized patients aged over 18 years who were diagnosed with cirrhosis of the liver. Diagnosis was based on a combination of clinical evaluation. Patients included in the study had hyponatremia, defined as serum sodium ≤130 meq/L on admission, with resolution during hospitalization to ≥135 meq/L.Patients were excluded if they had acute kidney injury (creatinine >1 mg/dl) or hepatorenal syndrome, symptomatic or severe hyponatremia (serum sodium <120 meq/L), HIV infection, prior liver transplant, chronic kidney disease, congestive heart failure, pregnancy, malignancy, acute on chronic liver failure (ACLF), allergy to albumin, urinary sodium >20 meq/L, or were critically ill. Additionally, patients who were unable to provide consent were excluded from the study. The study was designed as a prospective observational study to systematically evaluate the selected population

Table 1:-Comparison of demographic characteristics between with and without albumin group. Demographic characteristics With albumin group(n=25) Without albumin group(n=25) Total P value Age(years) Mean ± SD 52.52 ± 12.09 50.88 ± 12.04 51.7 ± 11.97 0.633* Median(25th- 75th percentile) 50(45-59) 48(45-56) 49.5(45-58) Range 26-77 27-78 26-78 Gender Female 1 (4%) 6 (24%) 7 (14%) 0.098‡ Male 24 (96%) 19 (76%) 43 (86%) In our study distribution of gender was comparable between with and without albumin group. (Female:- 4% vs 24% respectively, Male:- 96% vs 76% respectively) (p value=0.098). In our study age(years) in the albumin group was 52.52 ± 12.09 and in the without albumin group was 50.88 ± 12.04 with no significant difference between them. (p value=0.633) Table 2:-Comparison of etiology between with and without albumin group. Etiology With albumin group(n=25) Without albumin group(n=25) Total P value Ethanol 13 (52%) 17 (68%) 30 (60%) 0.306‡ NAFLD 9 (36%) 5 (20%) 14 (28%) Autoimmune 1 (4%) 2 (8%) 3 (6%) Hepatitis B 2 (8%) 0 (0%) 2 (4%) HCV 0 (0%) 1 (4%) 1 (2%) Total 25 (100%) 25 (100%) 50 (100%) In the majority (30(60.00%)) of patients, etiology was ethanol followed by NAFLD (14(28.00%)), autoimmune (3(6.00%)) and hepatitis B (2(4.00%)). Etiology was HCV in only 1 out of 50 patients (2.00%). Table 3:-Comparison of serum albumin(g/dL) between with and without albumin group. Serum albumin(g/dL) With albumin group(n=25) Without albumin group(n=25) Total P value At day 1 Mean ± SD 2.51 ± 0.42 2.41 ± 0.62 2.46 ± 0.53 0.509* Median(25th- 75th percentile) 2.5(2.2-2.8) 2.4(1.9-3) 2.45(2.025- 2.975) Range 1.7-3.1 1.2-3.4 1.2-3.4 At day 5 Mean ± SD 2.79 ± 0.37 2.39 ± 0.62 2.59 ± 0.54 0.008* Median(25th- 75th percentile) 2.8(2.6-3) 2.4(1.9-3) 2.65(2.2-3) Range 2-3.4 1.2-3.3 1.2-3.4 Intra group p value wrt day 1 <.0001** 0.011** - - In our study, serum albumin levels were similar at day 1 between the albumin and without-albumin groups (2.51 ± 0.42 vs 2.41 ± 0.62, p=0.509), but by day 5, levels significantly increased in the albumin group (2.79 ± 0.37) and decreased in the without-albumin group (2.39 ± 0.62, p=0.008). The albumin group showed a significant rise from day 1 to day 5 (p<0.0001), whereas the without-albumin group experienced a significant decline (p=0.011). Table 4:-Comparison of serum sodium(mEq/L) between with and without albumin group. Serum sodium(mEq/L) With albumin group(n=25) Without albumin group(n=25) Total P value At day 1 Mean ± SD 124.96 ± 2.26 125.36 ± 2.27 125.16 ± 2.25 0.306† Median(25th-75th percentile) 125(124-126) 126(124-126) 125(124-126) Range 121-130 120-129 120-130 At day 5 Mean ± SD 132.84 ± 3.87 127.44 ± 4.37 130.14 ± 4.91 <.0001† Median(25th-75th percentile) 135(131-136) 126(124-129) 129(126-135) Range 125-138 121-136 121-138 Intra group p value wrt day 1 <.0001¶ 0.012¶ - - Improvement at day 5 Mean ± SD 8.28 ± 3.95 2.24 ± 3.33 5.26 ± 4.73 <.0001† Median(25th-75th percentile) 10(4-10) 1(0-3) 4(1-10) Range 1-15 -2-10 -2-15 In our study, serum sodium levels were similar at day 1 between the albumin and without-albumin groups (125 [124–126] vs 126 [124–126], p=0.306), but by day 5, levels and improvement were significantly higher in the albumin group (135 [131–136], improvement 10 [4–10]) compared to the without-albumin group (126 [124–129], improvement 1 [0–3], p<0.0001). Both groups showed a significant rise from day 1 to day 5, with greater improvement in the albumin group (p<0.0001) than in the without-albumin group (p=0.012). Table 5:-Comparison of hyponatremia resolution between with and without albumin group. Hyponatremia resolution With albumin group(n=25) Without albumin group(n=25) Total P value No 11 (44%) 20 (80%) 31 (62%) 0.009§ Yes 14 (56%) 5 (20%) 19 (38%) Total 25 (100%) 25 (100%) 50 (100%) In our study proportion of patients with hyponatremia resolution was significantly higher in albumin group as compared to without albumin group. (56% vs 20% respectively, p value=0.009). Table 6:-Multivariate linear regression to find out the factors affecting Improvement in serum sodium (mEq/L). Variables Beta coefficient Standard error P value Lower bound (95%) Upper bound (95%) Systolic blood pressure(mmHg) 0.088 0.077 0.261 -0.068 0.243 Diastolic blood pressure(mmHg) -0.085 0.108 0.433 -0.302 0.132 Serum creatinine(mg/dL) 0.944 3.137 0.765 -5.374 7.262 Group Without albumin group 1.000 With albumin group 3.979 1.088 0.001 1.788 6.170 On performing multivariate regression, the albumin group was a significant independent factor affecting improvement in serum sodium (mEq/L) after adjusting for confounding factors. Patients in the albumin group had significantly high improvement in serum sodium(mEq/L) with an adjusted beta coefficient of 3.979(6.17 to 0). Table 7:-Multivariate logistic regression to find out the factors affecting resolution of hyponatremia. Hyponatremia resolution Beta coefficient Standard error P value Odds ratio Odds ratio Lower bound (95%) Odds ratio Upper bound (95%) EGFR(mL/min/1.73m²) -0.002 0.013 0.864 0.998 0.973 1.023 Serum sodium(mEq/L) at day 1 0.211 0.156 0.175 1.235 0.910 1.676 Group Without albumin group 1.000 With albumin group 1.634 0.660 0.013 5.123 1.405 18.676 On performing multivariate regression, the albumin group was a significant independent factor of hyponatremia resolution after adjusting for confounding factors. Patients in the albumin group had significantly high chance of hyponatremia resolution with adjusted odds ratio of 5.123(1.405 to 18.676).

In our study distribution of gender was comparable between with and without albumin group. (Female:- 4% vs 24% respectively, Male:- 96% vs 76% respectively) (p value=0.098). In our study age(years) in the albumin group was 52.52 ± 12.09 and in the without albumin group was 50.88 ± 12.04 with no significant difference between them. (p value=0.633) In our study the etiology of cirrhosis of the liver was alcohol (60%), NAFLD (28%), autoimmune(6%), hepatitis B (4%) and hepatitis C(2%). Most common etiology was alcohol related. Similar results was found in study done by Brij Sharma et al8 they observed that alcohol was the leading cause of cirrhosis in our study (62.9%), hepatitis B was the second(10.1%), Non-Alcoholic Steatohepatitis (NASH) was the third (7.9%), and autoimmune the fourth (3.9%) most common cause for cirrhosis. In our study, serum sodium at day 5 and its improvement were significantly higher in the albumin group (135 [131–136], improvement 10 [4–10]) compared to the without-albumin group (126 [124–129], improvement 1 [0–3], p<0.0001). Additionally, the proportion of patients achieving hyponatremia resolution was significantly greater in the albumin group than in the without-albumin group (56% vs 20%, p=0.009).Similar results was found in study done by Bajaj et al9 in hyponatremic patients who received albumin there was a significantly higher rate of hyponatraemia resolution(69% vs 61%, p<0.05) compared to hyponatremic patients not given albumin respectively. In our study significant increase in serum sodium (mEq/L) at day 5 as compared to day 1 in with albumin group was (mean delta sodium=8.28)(p value<.0001) and in without albumin group(mean delta sodium=2.24) (p value=0.012). Multivariate regression analysis showed that after adjusting all the confounding factors (EGFR and serum sodium at admission), patients on iv albumin showed significant hyponatremia resolution (OR- 5.123) as compared to patients in without albumin group. Similar results was observed by Bajaj et al.9 They observed that the difference remained significant even after adjustment for admission Na and EGFR. In our study, MELD-Na at day 5 and its improvement were significantly better in the albumin group, with lower mean values (20.4 ± 4.21 vs 24.28 ± 2.84, p=0.0004) and greater decrease (4.16 ± 2.32 vs 0.44 ± 1.69, p<0.0001) compared to the without-albumin group. This indicates that intravenous albumin, especially in hyponatremic patients awaiting liver transplantation, is beneficial. Additionally, serum albumin levels significantly increased from day 1 to day 5 in the albumin group (p<0.0001).Similar observation was found in study done by Louise China et al10 the primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. They found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. In view improvement in serum sodium and serum albumin after treated with albumin we also calculate a new score MELD 3.0. In a study done by W Ray Kim11 they observed that the final model (MELD 3.0) had better discrimination than MELD Na (C-statistic, 0.869 vs 0.862; P < .01). In our study we not only observed the effect of intravenous albumin on hyponatremia resolution but also observed that improvement in MELD Na. We also calculated a new score MELD 3.0 which was statistically significantly improved with albumin treatment and they both are predictors of mortality. Fukuhara et al.12 observed that pretransplant hyponatremia was a significant risk factor for short-term graft loss and postoperative complications including sepsis, renal failure and neurological disorders.

Our study demonstrates the beneficial effect of intravenous albumin infusion in improving hyponatremia in decompensate cirrhotic patients with hyponatremia. We also observed that intravenous albumin improves MELD-Na and MELD 3.0. Hence we conclude that intravenous albumin should be used specifically in hyponatremic end stage liver disease patients irrespective of its cost because it not only improves hyponatremia but also definitely benefits in short term and long term mortality.

1. Patrick S, Kamath, Vijay H, Shah “Overview of Cirrhosis” Sleisenger and Fordtran’s Gastrointestinal and Liver Disease 2015;74:1254-60. 2. Arroyo V, Rodés J, Gutiérrez-Lizárraga MA, Revert L. “Prognostic value of spontaneous hyponatremia in cirrhosis of liver with ascites” Am J Dig Dis. 1976;21:249–56. 3. Ginès P, Guevara M. “Hyponatremia in cirrhosis of liver: Pathogenesis, clinical significance, and managemen” Hepatology. 2008;48:1002–10. 4. Angeli P, Wong F, Watson H, Ginès P CAPPS Investigators. “Hyponatremia in cirrhosis of liver: Results of a patient population survey” Hepatology. 2006;44:1535–42. 5. Arieff AI, Llach F, Massry SG. “Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes”. Medicine (Baltimore) 1976;55:121–9. 6. Groszmann RJ. “Hyperdynamic circulation of liver disease 40 years later:Pathophysiology and clinical consequences”. Hepatology. 1994;20:1359–63. 7. Schedl HP, Bartter FC. “An explanation for and experimental correction of the abnormal water diuresis in cirrhosis of liver”. J Clin Invest. 1960;39:248–61. 8. Brij Sharma, Rishab Marwah, Sujeet Raina, et aletiology of cirrhosis of liver in adults living in the Hills of Himachal Pradesh, India. Trop Gastroenterol. 2016;37(1):37-41. 9. Bajaj JS1, O'Leary JG2, Wong F3, Kamath PS4 “Variations in albumin use in patients with cirrhosis of liver” Hepatology 2015 Dec;62(6):1923-4. 10. Louise China, MD, Nick Freemantle, Ewan Forrest et al”Targeted Albumin Therapy Does Not Improve Short-Term Outcome in Hyponatremic Patients Hospitalized With Complications of Cirrhosis: Data From the ATTIRE Trial” Am J Gastroenterol 2021;116:2292–2295 11. Kim, W.R.; Biggins, S.W.; Kremers, et al Hyponatremia and mortality among patients on the liver-transplant waiting list. N. Engl. J. Med. 2008, 359, 1018–1026. 12. Fukuhara, T.; Ikegami, T.; Morita, K.; et al Y. Impact of preoperative serum sodium concentration in living donor liver transplantation. J. Gastroenterol. Hepatol. 2010, 25, 978–984.